SINCALIDE: 114 Adverse Event Reports & Safety Profile

Kinevac (sincalide for injection) is a cholecystopancreatic-gastrointestinal hormone for parenteral administration. The agent is a synthetically-prepared C-terminal octapeptide of cholecystokinin. Each single-dose vial of sincalide provides a sterile nonpyrogenic lyophilized white powder consisting of 5 mcg sincalide with 30 mg arginine hydrochloride, 15 mg lysine hydrochloride, 170 mg mannitol, 4 mg methionine, 2 mg pentetic acid, 0.005 mcg polysorbate 20, 9 mg potassium phosphate dibasic, and 0.04 mg sodium metabisulfite. The pH is adjusted to 6.0 to 8.0 with hydrochloric acid and/or sodium hydroxide prior to lyophilization. Sincalide is designated chemically as L-α-aspartyl-O-sulfo-L-tyrosyl-L-methionylglycyl-L-tryptophyl-L-methionyl- L-α-aspartyl-L-phenylalaninamide. Graphic formula: kinevac-struct

AND USAGE Sincalide for Injection is indicated in adults to: to stimulate gallbladder contraction, as may be assessed by various methods of diagnostic imaging, or to obtain by duodenal aspiration a sample of concentrated bile for analysis of cholesterol, bile salts, phospholipids, and crystals; to stimulate pancreatic secretion in combination with secretin prior to obtaining a duodenal aspirate for analysis of enzyme activity, composition, and cytology; to accelerate the transit of a barium meal through the small bowel, thereby decreasing the time and extent of radiation associated with fluoroscopy and x-ray examination of the intestinal tract. Sincalide for Injection is a cholecystokinin (CCK) analog indicated in adults to: stimulate gallbladder contraction, as may be assessed by various methods of diagnostic imaging, or to obtain by duodenal aspiration a sample of concentrated bile for analysis of cholesterol, bile salts, phospholipids, and crystals. ( 1 ) stimulate pancreatic secretion in combination with secretin prior to obtaining a duodenal aspirate for analysis of enzyme activity, composition, and cytology. ( 1 ) accelerate the transit of a barium meal through the small bowel, thereby decreasing the time and extent of radiation associated with fluoroscopy and x-ray examination of the intestinal tract. ( 1 )

AND ADMINISTRATION Recommended Adult Dosage and Administration by Indication: To Stimulate Contraction of the Gallbladder 0.02 mcg/kg as a single dose over 30 to 60 seconds via intravenous injection. If satisfactory contraction does not occur in 15 minutes, administer a dose of 0.04 mcg/kg over 30 to 60 seconds. ( 2.1 ) Alternatively consider an intravenous infusion to reduce gastrointestinal adverse reactions : 0.12 mcg/kg diluted in 100 mL of 0.9% Sodium Chloride Injection USP and infused over 50 minutes at a rate of 2 mL per minute. ( 2.1 , 2.2 , 5.3 )

To Stimulate Pancreatic

Secretion in Combination with Secretin 30 minutes after initiation of secretin for injection, administer 0.02 mcg/kg diluted in 30 mL of 0.9% Sodium Chloride Injection USP and infused over 30 minutes at a rate of 1 mL per minute. ( 2.1 , 2.2 )

To Accelerate

Transit of a Barium Meal Through the Small Intestine After the barium meal is beyond the proximal jejunum, administer 0.04 mcg/kg over 30 to 60 seconds via intravenous injection. ( 2.1 ) If satisfactory transit of the barium meal has not occurred in 30 minutes, administer a second dose of 0.04 mcg/kg over 30 to 60 seconds. ( 2.1 ) Alternatively consider an intravenous infusion to reduce gastrointestinal adverse reactions : 0.12 mcg/kg diluted in 100 mL 0.9% Sodium Chloride Injection USP and infused over 30 minutes. ( 2.1 , 2.2 , 5.3 )

2.1 Recommended Dosage and Administration Instructions The recommended dosage and administration of Sincalide for Injection by indication is shown in Table 1. For preparation instructions see Dosage and Administration ( 2.2 ) .

Table

1: Recommended Adult Dosage and Administration of Sincalide for Injection by Treatment Indication Indication Recommended Adult Dosage and Administration of Sincalide for Injection To stimulate contraction of the gallbladder Sincalide for Injection 0.02 mcg/kg as a single dose over 30 to 60 seconds via intravenous injection. If satisfactory contraction does not occur in 15 minutes, administer a dose of 0.04 mcg/kg over 30 to 60 seconds. Alternatively, Consider an Intravenous Infusion to Reduce Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.3 )] : 0.12 mcg/kg diluted in 100 mL of 0.9% Sodium Chloride Injection USP and infused over 50 minutes at a rate of 2 mL per minute. To stimulate pancreatic secretion in combination with secretin for injection Secretin for Injection: 0.25 units/kg as intravenous infusion over 60 minutes Sincalide for Injection: 30 minutes after initiation of secretin infusion, administer Sincalide for Injection 0.02 mcg/kg diluted in 30 mL of 0.9% Sodium Chloride Injection USP and infused over 30 minutes at a rate of 1 mL per minute. To accelerate the transit of a barium meal through the small intestine After the barium meal is beyond the proximal jejunum, administer Sincalide for Injection 0.04 mcg/kg over 30 to 60 seconds via intravenous injection. If satisfactory transit of the barium meal has not occurred in 30 minutes, administer a second dose of 0.04 mcg/kg over 30 to 60 seconds. Alternatively, Consider an Intravenous Infusion to Reduce Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.3 )] : 0.12 mcg/kg diluted in 100 mL 0.9% Sodium Chloride Injection USP and infused over 30 minutes.

2.2 Preparation Instructions For Intravenous Injection Reconstitute Sincalide for Injection aseptically by adding 5 mL of Sterile Water for Injection USP to the vial. Inspect the reconstituted solution visually for particulate matter and discoloration after reconstitution and prior to administration. Withdraw the prescribed dose of the reconstituted solution from the vial and administer as an intravenous injection over 30 to 60 seconds, as shown in Table 1. Discard the unused portion. Store the reconstituted solution at room temperature. Discard after 8 hours. For single use only; discard unused portion.

For Intravenous Infusion Reconstitute

Sincalide for Injection aseptically by adding 5 mL of Sterile Water for Injection USP to the vial. After reconstitution, withdraw the prescribed dose of the solution from the vial. Discard unused portion. Dilute the reconstituted solution in 30 mL or 100 mL of 0.9% Sodium Chloride Injection USP, depending on the indication, as described in Table 1. Inspect the Sincalide for Injection solutions visually for particulate matter and discoloration after reconstitution, dilution and prior to administration. Store the diluted solution at room temperature. Discard after 1 hour .

Sincalide for Injection is contraindicated in patients with: a history of a hypersensitivity reaction to sulfites or sincalide. Serious hypersensitivity reactions have included anaphylaxis and anaphylactic shock [see Warnings and Precautions (5.1), Adverse Reactions (6)]. intestinal obstruction. History of hypersensitivity to sulfites or sincalide. ( 4 , 5.1 ) Intestinal obstruction. ( 4 )

REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions [see Warnings and Precautions ( 5.1 )] Evacuation of gallstones [see Warnings and Precautions ( 5.2 )] Adverse reactions with intravenous injection [see Warnings and Precautions ( 5.3 )] Preterm labor or spontaneous abortion [see Warnings and Precautions ( 5.4 )] The following adverse reactions associated with the use of Sincalide for Injection were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency, reliably, or to establish a causal relationship to drug exposure. The most frequent adverse reactions (20% or greater) are gastrointestinal: abdominal discomfort or pain, and nausea; these may not necessarily indicate an abnormality of the biliary tract unless there is other clinical or radiologic evidence of disease. Less common adverse reactions include: Hypersensitivity reactions : anaphylaxis and anaphylactic shock, hypotension, throat tightness, bradycardia, shortness of breath, nausea, abdominal cramping, diaphoresis, hives, rash, itching; and numbness of face, lips and eyes [see Contraindications ( 4 ), ( 5.1 )] . Neurological reactions : seizures, headache. Vasovagal reactions : dizziness, loss of consciousness, nausea, diaphoresis, syncope and hypotension (generally self-limiting). Other: nausea, vomiting, flushing, hypertension, urge to defecate, diarrhea, sneezing. Most common adverse reactions (≥20%) are: abdominal discomfort or pain, and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

AND PRECAUTIONS Anaphylaxis, Anaphylactic Shock and Other Serious Hypersensitivity Reactions: Contains sodium metabisulfite. Serious reactions may occur during or soon after administration. If symptoms occur, discontinue the drug. ( 4 , 5.1 ) Evacuation of Gallstones : Stimulation of gallbladder contraction in patients with small gallbladder stones could lead to the evacuation of the stones from the gallbladder, resulting in their lodging in the cystic duct or in the common bile duct. ( 5.2 )

Gastrointestinal Adverse

Reactions with Intravenous Injection : Administration as an intravenous injection may cause transient nausea, vomiting, abdominal pain or cramping, dizziness or flushing. To reduce the risk of adverse reactions when used to stimulate contraction of the gallbladder or accelerate transit of a barium meal through the small intestine, administer as an intravenous infusion over 50 or 30 minutes, respectively. ( 2.1 , 5.3 )

Preterm

Labor or Spontaneous Abortion : Advise pregnant women of the potential risk for preterm labor and spontaneous abortion. ( 5.4 , 8.1 )

5.1 Anaphylaxis, Anaphylactic Shock and Other Serious Hypersensitivity Reactions Contains sodium metabisulfite <span class="opacity-50 text-xs">[see Description ( 11 )]</span> , a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people. In postmarketing experience, anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions have been reported during and within one hour following administration of Sincalide for Injection <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . Sincalide for Injection is contraindicated in patients with a history of hypersensitivity to sulfites. Due to the potential for anaphylaxis, appropriate medical support should be readily available when Sincalide for Injection is administered. If anaphylaxis or other hypersensitivity reactions occur, immediately discontinue the infusion and initiate appropriate medical treatment. Observe patients closely during and after the infusion. Do not reinitiate Sincalide for Injection in patients who have experienced symptoms of hypersensitivity <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

5.2 Evacuation of Gallstones Stimulation of gallbladder contraction in patients with small gallbladder stones could lead to the evacuation of the stones from the gallbladder, resulting in their lodging in the cystic duct or in the common bile duct.

5.3 Gastrointestinal Adverse Reactions with Intravenous Injection Administration of Sincalide for Injection as an intravenous injection may cause adverse reactions such as nausea, vomiting, abdominal pain or cramping, dizziness, and flushing <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . These reactions are generally transient. To reduce the risk of adverse reactions with intravenous injection when used to stimulate contraction of the gallbladder or accelerate transit of a barium meal through the small intestine, administer Sincalide for Injection as an intravenous infusion over 50 or 30 minutes, respectively <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span>.

5.4 Preterm Labor or Spontaneous Abortion Because of Sincalide for Injection&apos;s effect on smooth muscle, pregnant patients should be advised that spontaneous abortion or premature induction of labor may occur <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> .

INTERACTIONS Drugs that Affect Gallbladder Motility or Contractile Response : May interfere with response to sincalide. Consider discontinuing these drugs prior to administration of Sincalide for Injection, when used to stimulate contraction of the gallbladder. ( 7.1 )

7.1 Drugs that Affect Gallbladder Motility or Contractile Response Drugs that may stimulate or inhibit gallbladder motility or contractile response, may interfere with the response to sincalide. Consider discontinuing these drugs prior to administration of Sincalide for Injection, when used to simulate contraction of the gallbladder.